Heart failure (HF) is a pathological condition in which the heart is unable to pump blood at a rate required for normal metabolism and physical activity. Frequently, the exact causes of HF (particularly chronic HF) are unknown, but may be one or more of hypertension, myocardial injury, ischemic heart disease, cardiac valve abnormalities, coronary artery diseases, and abnormal electrical conduction within the heart. Alone or in combination, these conditions cause an increased chronic load on the heart which triggers three major compensatory mechanisms: the adrenergic system, the renin-angiotensin-aldosterone system, and ventricular hypertrophy. Although these mechanisms allow the heart to adapt and maintain adequate cardiac output, over time, they also bring about deleterious effects on the heart and cardiovascular system. These deleterious effects include cardiac myocyte hypertrophy leading to wall thickening and reduced contractility, elevated cytosolic calcium, causing impaired myocardial relaxation, vasoconstriction and aldosterone-induced salt and water retention, both of which may cause hypertension and additional load on the heart.
In current medical practice, patients are treated with one or more drugs that reduce stress on the heart. These drugs include vasodilators, diuretics, angiotensin receptor blockers, and beta-blockers. In combination with a healthy life style, these drug regimens improve symptoms and quality of life for the patient. Nevertheless, the pathophysiological changes in the heart progress over time causing debilitation of the heart and decreasing mobility and declining quality of life for the patient.
Poloxamer 188 (“P-188” or “P188”) has been shown to improve cardiac output and reverse the heart failure associated with muscular dystrophy. Cardiac muscle cells exhibited a contractile defect that resulted from sustained high levels of cytosolic calcium. P-188, when added to an in vitro cardiac muscle preparation, appeared to seal tears in the muscle cell membrane, and thereby prevent an influx of calcium and allow cells to normalize their calcium levels. All of these affects of P-188 on cardiac muscle cells were observed in vitro, by placing the cell in a solution containing a fairly high concentration of P-188. Following exposure to P-188 treatment, heart muscle exhibited an improved ability to relax (improved diastolic function) and increased cardiac output. Furthermore, it is unknown whether these results are applicable to heart failure other than that associated with muscular dystrophy.
It would be desirable, to provide a treatment for heart failure that would slow or reverse the pathophysiological changes of the cardiac muscle tissue and could be administered intermittently but have a continuous therapeutic effect. Such a treatment would overcome many of the limitations and disadvantages inherent in the presently available treatments described above.